Glioblastoma multiforme (GBM) is one of the most deadly cancers for which no effective treatment strategy currently exists. The primary cilium is a ubiquitous microtubule based organelle that protrudes from the apical surface of most human cells serving as a cellular antenna for signal transduction and an important regulator of the mitosis. The cilia are lost in many types of cancer including GBM (1-7). The importance of cilia loss for cancer progression is largely unknown, although several attempts to rescue ciliation in cancer cells reveal the therapeutic benefit behind the primary cilia restoration (8, 9). Our long-term goal is to delineate the molecular mechanism of primary cilia disassembly under normal and pathological conditions and determine if the loss of cilium is required for cancer progression. This knowledge is critical for the development of new therapeutic strategies to prevent and eradicate tumor growth. Aurora kinase A (AURKA AurA), a common proto-oncogene often overexpressed in GBM (10-13), initiates rapid cilia disassembly (8, 14), but the downstream effectors of this pathway still have not been found. One of the potential AURKA effectors is the motor protein KIF2C, known to directly destabilize microtubules. The objectives of this application are to decipher the molecular mechanism/s of the KIF2C-driven cilium disassembly and to determine therapeutic benefits of cilium restoration in GBM patient derived xenograft (PDX) models. Our central hypothesis is that AURKA-dependent activation of KIF2C leads to cilia disassembly, resulting in an increase in cell proliferation and tumor progression. Rescue of ciliation will inhibit proliferation, disease progression and potentially recurrence. We will test our hypothesis through the execution of following aims:
Aim #1 : Determine the mechanism/s of KIF2C driven deciliation. Our working hypothesis is that AURKA phosphorylation promotes KIF2C translocation from the cytoplasm to the primary cilium, where it orchestrates the disassembly of axonemal microtubules.
Aim #2 : Determine the therapeutic benefits of combination therapy of KIF2C depletion and AURKA inhibition in the treatment of glioblastoma in patient-derived xenograft (PDX) models. Our hypothesis is that the combination of KIF2C depletion and inhibition of AURKA will synergistically increase the incidence of primary cilia in cancer cells, and decrease tumor growth and potentially recurrence. The rationale for the proposed work is that it will elucidate new mechanisms driving cilia disassembly and provide insight into the critical role of the primary cilia in cancer progression, and reveal new strategies for a targeted treatment of cancer.
The proposed research seeks to establish the molecular mechanism underlining ciliary disassembly and its connection with tumor progression via the regulation of KIF2C. The goal is to deliver a new approach to anti- cancer therapy for glioblastoma, and potentially other cancers. The completion of this project is expected to provide new knowledge into the understanding of cancer-driven deciliation and improve the disease outcome for glioblastoma patients.
|Loskutov, Yuriy V; Griffin, Caryn L; Marinak, Kristina M et al. (2018) LPA signaling is regulated through the primary cilium: a novel target in glioblastoma. Oncogene 37:1457-1471|
|Loskutov, Y V; Kozyulina, P Y; Kozyreva, V K et al. (2015) NEDD9/Arf6-dependent endocytic trafficking of matrix metalloproteinase 14: a novel mechanism for blocking mesenchymal cell invasion and metastasis of breast cancer. Oncogene 34:3662-75|